Neurotransplantation of stem cells genetically modified to express human dopamine transporter reduces alcohol consumption

We have generated a neural stem cell line stably expressing the hDAT. Uptake kinetics of DA were determined to select a clone for transplantation. These genetically modified stem cells (or cells transfected with a construct lacking the hDAT sequence) were transplanted bilaterally into the NAC of wild-type mice trained to consume 10% alcohol in a two-bottle free-choice test for alcohol consumption. Alcohol intake was then ascertained for 1 week after transplantation, and brain sections through the NAC were examined for surviving grafted cells.Modified stem cells expressed hDAT and uptaken DA selectively via hDAT. Mice accustomed to drinking 10% ethanol by free choice reduced their alcohol consumption after being transplanted with hDAT-expressing stem cells. By contrast, control stem cells lacked that effect. Histologic examination revealed surviving stem cells in the NAC of all engrafted brains.Our findings represent proof of principle suggesting that genetically engineered stem cells can be useful for exploring the role of neurotransmitters (or other signaling molecules) in alcohol consumption and potentially in other aspects of brain function.It has been 50 years since Olds and Milner [1] described the existence of reward pathways in the brain, based on their experiments showing that electrical stimulation of certain brain areas is rewarding to rats. Today's understanding of common reward pathways in the brain involves the mesocorticolimbic circuitry consisting of dopaminergic cell bodies in the ventral tegmental area (VTA) and their projections to terminal areas of the prefrontal cortex and the "extended amygdala" (the NAC, substantia innominata, bed nucleus of the stria terminalis and amygdala). Rewarding stimuli such as food, sex, and drugs of abuse, including ethanol, result in the release of DA in terminal areas, particularly the NAC [2]. Although the dopaminergic mesocorticolimbic pathway is clearly involved in reward mechanisms, questions about the precise r